Immunosuppressive agents are widely used in the treatment of autoimmune disease and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD). Common immunosuppressive agents include azathioprine, corticosteroids, cyclophosphamide, methotrexate, 6-mercaptopurine, vincristine, and cyclosporin A. In general, none of these drugs are completely effective, and most are limited by severe toxicity. For example, cyclosporin A, a widely used agent, is significantly toxic to the kidney. In addition, doses needed for effective treatment may increase the patient's susceptibility to infection by a variety of opportunistic invaders.
The compound triptolide, obtained from the Chinese medicinal plant Tripterygium wilfordii (TW), and certain derivatives and prodrugs thereof, have been identified as having immunosuppressive activity, e.g. in the treatment of autoimmune disease, and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD). See, for example, co-owned U.S. Pat. Nos. 5,962,516 (Immunosuppressive compounds and methods), 5,843,452 (Immunotherapy composition and method), 5,759,550 (Method for suppressing xenograft rejection), 5,663,335 (Immunosuppressive compounds and methods), 5,648,376 (Immunosuppressant diterpene compound), and 6,150,539 (Triptolide prodrugs having high aqueous solubility), which are incorporated by reference. Triptolide and certain derivatives and prodrugs thereof have also been reported to show anticancer activity; see, for example, Kupchan et al., 1972, 1977, as well as co-owned U.S. Pat. No. 6,620,843 (September 2003), which is hereby incorporated by reference.
Although derivatives and prodrugs of triptolide have provided benefits relative to native triptolide in areas such as pharmacokinetics or biodistribution, e.g. by virtue of differences in lipid or aqueous solubility, or via their activity as prodrugs, the biological activity per se of triptolide derivatives is often significantly less than that of native triptolide.